Abipim®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ABYPIME® (ABYPIME®)

Composition:

Active substance: cefepime;

1 vial contains cefepime 500 mg or 1000 mg (as a sterile mixture of cefepime hydrochloride and L-arginine).

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: powder from white to light yellow in color.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. β-lactam antibiotics.

ATC code J01D E01.

Pharmacological Properties

Pharmacodynamics

Cefepime is a fourth-generation β-lactam cephalosporin antibiotic with a broad spectrum of activity for parenteral administration. It exerts a bactericidal effect. It is active against Gram-positive and Gram-negative bacteria, including most strains resistant to aminoglycosides or third-generation cephalosporins such as ceftazidime. Cefepime is highly stable to the action of most β-lactamases and rapidly penetrates Gram-negative bacteria. The binding affinity of cefepime to penicillin-binding protein PBP 3 significantly exceeds that of other parenteral cephalosporins. Moderate affinity of cefepime to PBP 1a and 1b also contributes to its level of bactericidal activity. The MBC (minimum bactericidal concentration)/MIC ratio for cefepime is less than 2 for more than 80% of isolates of all susceptible Gram-positive and Gram-negative bacteria.

Cefepime inhibits the synthesis of bacterial cell wall enzymes and has a broad spectrum of activity against various Gram-positive and Gram-negative bacteria. Cefepime is highly resistant to hydrolysis by most β-lactamases, has low affinity for chromosomally encoded β-lactamases, and rapidly penetrates Gram-negative bacterial cells.

Cefepime is active against the following microorganisms:

Gram-positive aerobes: Staphylococcus aureus (including β-lactamase-producing strains), Staphylococcus epidermidis (including β-lactamase-producing strains), other staphylococcal strains (including S. hominis, S. saprophyticus), Streptococcus pyogenes (Group A), Streptococcus agalactiae (Group B), Streptococcus pneumoniae (including strains with intermediate penicillin resistance—MIC 0.1 to 0.3 mcg/mL), other β-hemolytic streptococci (Groups C, G, F), S. bovis (Group D), Viridans group streptococci. (Most enterococcal strains, e.g., Enterococcus faecalis, and methicillin-resistant staphylococci are resistant to most cephalosporin antibiotics, including cefepime.)

Gram-negative aerobes: Pseudomonas spp. (including P. aeruginosa, P. putida, P. stutzeri), Escherichia coli, Klebsiella spp. (including K. pneumoniae, K. oxytoca, K. ozaenae), Enterobacter spp. (including E. cloacae, E. aerogenes, E. sakazakii), Proteus spp. (including P. mirabilis, P. vulgaris), Acinetobacter calcoaceticus (including subspecies Anitratus, Iwoffi), Aeromonas hydrophila, Capnocytophaga spp., Citrobacter spp. (including C. diversus, C. freundii), Campylobacter jejuni, Gardnerella vaginalis, Haemophilus ducreyi, H. influenzae (including β-lactamase-producing strains), H. parainfluenzae, Hafnia alvei, Legionella spp., Morganella morganii, Moraxella catarrhalis (Branhamella catarrhalis) (including β-lactamase-producing strains), Neisseria gonorrhoeae (including β-lactamase-producing strains), N. meningitidis, Providencia spp. (including P. rettgeri, P. stuartii), Salmonella spp., Serratia (including S. marcescens, S. liquefaciens), Shigella spp., Yersinia enterocolitica. Cefepime is inactive against many strains of Xanthomonas (Pseudomonas) maltophilia.

Anaerobes: Bacteroides spp. (including B. melaninogenicus and other oral cavity microorganisms belonging to Bacteroides), Clostridium perfringens, Fusobacterium spp., Mobiluncus spp., Peptostreptococcus spp., Veillonella spp. Cefepime is inactive against Bacteroides fragilis and Clostridium difficile.

Pharmacokinetics

Cefepime is completely absorbed after intramuscular administration.

Mean plasma concentrations of cefepime in healthy adult patients after single intravenous (i.v.) and intramuscular (i.m.) administration are shown in the table.

Mean plasma concentrations of cefepime (mcg/mL):

Cefepime dose	0.5 hour	1 hour	2 hours	4 hours	8 hours	12 hours
500 mg IV	38.2	21.6	11.6	5.0	1.4	0.2
1 g IV	78.7	44.5	24.3	10.5	2.4	0.6
2 g IV	163.1	85.8	44.8	19.2	3.9	1.1
500 mg IM	8.2	12.5	12.0	6.9	1.9	0.7
1 g IM	14.8	25.9	26.3	16.0	4.5	1.4
2 g IM	36.1	49.9	51.3	31.5	8.7	2.3

Therapeutic concentrations of cefepime are achieved in urine, bile, peritoneal fluid, bronchial mucous secretions, sputum, prostate, appendix, and gallbladder.

The elimination half-life of cefepime is approximately 2 hours and is independent of dose within the range of 250 mg – 2 g. No drug accumulation was observed after intravenous administration of doses up to 2 g every 8 hours over 9 days.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to N-methylpyrrolidine oxide. Cefepime is primarily eliminated by glomerular filtration (total clearance of cefepime is approximately 120 mL/min, mean renal clearance is 110 mL/min). Approximately 80–85% of the administered dose is excreted in urine as unchanged cefepime, 1% as N-methylpyrrolidine, about 6.8% as N-methylpyrrolidine oxide, and about 2.5% as cefepime epimer. Protein binding of cefepime to plasma proteins is less than 19% and does not depend on drug concentration in serum.

Dose adjustment is not required for patients aged 65 years and older with normal renal function.

In patients with renal impairment, the elimination half-life of cefepime is prolonged, and a linear relationship is observed between total drug clearance and creatinine clearance. The elimination half-life in patients with severe renal dysfunction requiring hemodialysis is 13 hours, and 19 hours in those undergoing continuous ambulatory peritoneal dialysis. Dose adjustment should be individualized in patients with abnormal renal function.

The pharmacokinetics of cefepime are not altered in patients with hepatic dysfunction or cystic fibrosis. Dose adjustment is not required for these patients.

Pediatrics. Pharmacokinetic studies of cefepime were conducted in children aged 2 months to 11 years after single or multiple doses administered every 8 hours (n=29) and every 12 hours (n=13). After a single intravenous injection, the mean total body clearance and steady-state volume of distribution were 3.3 (1.0) mL/min/kg and 0.3 (0.1) L/kg, respectively. Excretion of unchanged cefepime in urine was 60.4 (30.4)% of the administered dose, and mean renal clearance was 2.0 (1.1) mL/min/kg. Age and sex of patients (25 boys and 17 girls) did not significantly affect total body clearance or volume of distribution when corrected for body weight. No drug accumulation was observed with a dosing regimen of 50 mg/kg every 12 hours (n=13), whereas maximum plasma concentration, area under the curve, and elimination half-life increased by approximately 15% at steady state with the regimen of 50 mg/kg every 8 hours. Cefepime exposure in children after intravenous administration of 50 mg/kg is similar to that in adults after a 2 g intravenous dose. After intramuscular administration, the median peak plasma concentration of cefepime at steady state was 68 µg/mL at 0.75 hours. Eight hours after intramuscular administration, the plasma concentration of cefepime averaged 6 µg/mL. Absolute bioavailability of cefepime after intramuscular injection averaged 82%.

Due to the inability to identify the causative pathogen and determine its antibiotic susceptibility, or when time is insufficient, cefepime may be used for empirical therapy because of its broad-spectrum antibacterial activity. In patients at risk of mixed aerobic-anaerobic infections, treatment with cefepime may be initiated in combination with an anti-anaerobic agent until the pathogen is identified.

Clinical characteristics.

Indications.

Adults.

Infections caused by microorganisms sensitive to the drug:

• respiratory tract infections, including pneumonia, bronchitis;
• skin and soft tissue infections;
• intra-abdominal infections, including peritonitis and biliary tract infections;
• gynecological infections;
• sepsis.

Empirical therapy in patients with febrile neutropenia.

Prevention of postoperative complications in intra-abdominal surgery.

Children.

• Pneumonia;
• urinary tract infections, including pyelonephritis;
• skin and soft tissue infections;
• sepsis;
• empirical therapy in patients with febrile neutropenia;
• bacterial meningitis.

Contraindications.

Hypersensitivity to cefepime or L-arginine, as well as to cephalosporin-class antibiotics, penicillins, or other β-lactam antibiotics.

Interaction with other medicinal products and other types of interactions.

When administering high doses of aminoglycosides concomitantly with cefepime, renal function should be closely monitored due to the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been reported after concomitant administration of other cephalosporins with diuretics such as furosemide.

Cefepime at concentrations from 1 to 40 mg/mL is compatible with the following parenteral solutions: 0.9% sodium chloride injection; 5% and 10% glucose injection; 6M sodium lactate injection; 5% glucose and 0.9% sodium chloride injection; Ringer’s lactate with 5% glucose injection.

To avoid potential drug interactions with other agents, cefepime solutions (as with most other β-lactam antibiotics) should not be administered simultaneously with metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate solutions. If co-administration of cefepime with these agents is necessary, each antibiotic should be administered separately.

Effect on laboratory test results.

Cefepime administration may result in false-positive glucose in urine tests when using Benedict’s reagent. It is recommended to use glucose tests based on the enzymatic glucose oxidation reaction.

Special precautions for use.

In patients at high risk of severe infections (e.g., patients with a history of bone marrow transplantation associated with impaired marrow function due to severe progressive haematological malignancy and profound neutropenia), monotherapy may be insufficient, and combination antimicrobial therapy is indicated.

It is essential to determine carefully whether the patient has previously experienced immediate-type hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other β-lactam antibiotics. Antibiotics should be administered with caution to all patients with any type of allergy, especially drug allergies. If an allergic reaction occurs, the drug should be discontinued immediately. Severe immediate-type hypersensitivity reactions may require administration of adrenaline and other supportive therapies.

Cases of pseudomembranous colitis have been reported with the use of nearly all broad-spectrum antibiotics. Therefore, pseudomembranous colitis must be considered in the differential diagnosis of diarrhoea occurring during cefepime therapy. Mild cases of colitis may resolve upon discontinuation of the drug; moderate to severe cases may require specific treatment.

Cefepime should be used with caution in patients with gastrointestinal disorders, particularly colitis.

As with other antibiotics, cefepime use may lead to the development of superinfection, and appropriate measures should be taken. In patients with impaired renal function (creatinine clearance < 60 mL/min), the dose of cefepime should be adjusted to compensate for reduced renal elimination. Prolonged elevated serum antibiotic concentrations may occur at standard doses in patients with renal impairment or other conditions that may compromise renal function; therefore, maintenance doses should be reduced when administering cefepime to such patients. The degree of renal impairment, severity of infection, and susceptibility of the causative organisms should be considered when determining the appropriate dosage.

During post-marketing surveillance, severe, life-threatening, or fatal adverse events have been reported, including encephalopathy (disturbances of consciousness, including confusion, hallucinations, stupor, and coma), myoclonus, and seizures. Most cases occurred in patients with impaired renal function who received doses exceeding the recommended dosage. Some cases occurred in patients receiving doses adjusted according to renal function. In most cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after haemodialysis.

Antibacterial agents alter the normal flora of the colon and may promote overgrowth of Clostridium difficile. Studies indicate that the toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis. Once pseudomembranous colitis is diagnosed, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis may resolve after discontinuation of the drug. In moderate to severe cases, consideration should be given to fluid and electrolyte replacement, protein supplementation, and administration of an antibacterial agent effective against Clostridium difficile.

Warnings.

It is unlikely that prescribing cefepime in the absence of proven or suspected bacterial infection, or for prophylactic use, will be beneficial, and such use may increase the risk of emergence of bacteria resistant to this drug. Prolonged use of cefepime (as with other antibiotics) may lead to the development of superinfection. The patient's condition should be re-evaluated regularly. If superinfection develops, appropriate measures should be initiated.

Many cephalosporins, including cefepime, have been associated with reduced prothrombin activity. Patients at risk include those with hepatic or renal dysfunction, malnourished patients, and those receiving prolonged courses of antimicrobial therapy. Prothrombin levels should be monitored in high-risk patients, and vitamin K should be administered if necessary.

During cefepime therapy, positive results in the direct Coombs test may occur. When performing haematological or transfusion procedures, including cross-matching blood or performing the Coombs test in newborns whose mothers received cephalosporin antibiotics before delivery, a positive Coombs test should be interpreted in the context of recent drug administration.

Cefepime (cefepime hydrochloride) should be administered with caution to patients with a history of gastrointestinal disorders, particularly colitis.

L-arginine has been shown to alter glucose metabolism and simultaneously increase serum potassium levels when administered at doses 33 times higher than the maximum recommended dose of cefepime. Effects at lower doses are currently unknown.

Use during pregnancy or breastfeeding.

Cefepime should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Cefepime is excreted in human milk in small amounts; therefore, breastfeeding should be discontinued during treatment with this drug.

Ability to affect reaction speed when driving or operating machinery.

Since adverse reactions affecting the central nervous system may occur during treatment, patients should refrain from driving or operating machinery.

Method of Administration and Dosage.

The usual dosage for adults is 1 g, which should be administered intravenously or intramuscularly every 12 hours. The usual duration of treatment is 7–10 days; severe infections may require longer treatment.

However, the dosage and route of administration vary depending on the sensitivity of the causative microorganisms, the severity of the infection, and the patient's renal function. Dosage recommendations for cefepime in adults are provided in the table.

When using lidocaine solution as a solvent for intramuscular administration, information regarding lidocaine safety should be taken into account, and a skin test for tolerance to lidocaine should be performed.

Uncomplicated and moderate urinary tract infections	500 mg – 1 g intravenously or intramuscularly	every 12 hours
Other uncomplicated and moderate infections	1 g intravenously or intramuscularly	every 12 hours
Severe infections	2 g intravenously	every 12 hours
Very severe and life-threatening infections	2 g intravenously	every 8 hours

For prevention of infections during surgical procedures. 2 g of the drug is administered intravenously over 30 minutes to adults 60 minutes before the start of surgery. After completion, an additional 500 mg of metronidazole is administered intravenously. Metronidazole solutions should not be administered simultaneously with cefepime. The infusion system should be flushed before administration of metronidazole.

During prolonged surgical procedures (exceeding 12 hours), a repeat dose of the same amount of the drug is recommended 12 hours after the first dose, followed by administration of metronidazole.

Renal function impairment. The dose of the drug must be adjusted in patients with impaired renal function (creatinine clearance less than 30 mL/min).

Recommended doses of cefepime for adults

Creatinine clearance (mL/min)	Recommended doses
> 50	Standard dosing appropriate to the severity of infection (see previous table), no dose adjustment required
	2 g every 8 hours	2 g every 12 hours		1 g every 12 hours	500 mg every 12 hours
30–50	Dose adjustment according to creatinine clearance
	2 g every 12 hours		2 g every 24 hours	1 g every 24 hours	500 mg every 24 hours
11–29	2 g every 24 hours		1 g every 24 hours	500 mg every 24 hours	500 mg every 24 hours
≤ 10	1 g every 24 hours		500 mg every 24 hours	250 mg every 24 hours	250 mg every 24 hours
Hemodialysis	500 mg every 24 hours		500 mg every 24 hours	500 mg every 24 hours	500 mg every 24 hours

If only serum creatinine concentration is known, creatinine clearance can be calculated using the formula below:

Men:

body weight (kg) × (140 − age)

creatinine clearance (mL/min) = ---------------------------------------------------;

72 × serum creatinine (mg/dL)

Women:

body weight (kg) × (140 − age)

creatinine clearance (mL/min) = --------------------------------------------------- × 0.85.

72 × serum creatinine (mg/dL)

During hemodialysis, approximately 68% of the drug dose is eliminated from the body over 3 hours. After each dialysis session, a supplemental dose equal to the initial dose should be administered. For continuous ambulatory peritoneal dialysis (CAPD), the drug may be used at the initial recommended doses of 500 mg, 1 g, or 2 g, depending on the severity of infection, with a 48-hour interval between doses.

Children aged 1–2 months should receive the drug only for life-threatening indications. The condition of children with body weight below 40 kg receiving cefepime therapy should be closely monitored.

For children with impaired renal function, a reduced dose or extended dosing interval is recommended.

Calculation of creatinine clearance in children:

0.55 × height (cm)

creatinine clearance (mL/min/1.73 m²) = --------------------------------

serum creatinine (mg/dL)

or

0.52 × height (cm)

creatinine clearance (mL/min/1.73 m²) = ------------------------------------------ – 3.6.

serum creatinine (mg/dL)

Children aged 1 to 2 months. The drug should be administered only for life-threatening indications at a dose of 30 mg/kg body weight every 12 or 8 hours, depending on the severity of infection.

Children aged 2 months and older. The maximum dose for children should not exceed the recommended adult dose. The usual recommended dose for children with body weight below 40 kg for complicated or uncomplicated urinary tract infections (including pyelonephritis), uncomplicated skin infections, pneumonia, and for empirical treatment of febrile neutropenia is 50 mg/kg every 12 hours (every 8 hours for patients with febrile neutropenia or bacterial meningitis). The usual duration of treatment is 7–10 days; severe infections may require longer treatment.

Children with body weight of 40 kg or more should receive doses as recommended for adults.

Administration of the drug. The drug can be administered intravenously or by deep intramuscular injection into a large muscle mass (e.g., the upper outer quadrant of the gluteal muscle – gluteus maximus).

Intravenous administration. The intravenous route is preferred for patients with severe or life-threatening infections.

For intravenous administration, cefepime should be dissolved in sterile water for injection, 5% dextrose solution for injection, or 0.9% sodium chloride solution for injection, as specified in the table below. It should be administered intravenously slowly over 3–5 minutes or via an intravenous infusion system.

Intramuscular administration. The drug can be reconstituted with sterile water for injection, 0.9% sodium chloride solution for injection, 5% dextrose solution for injection, bacteriostatic water for injection with parabens or benzyl alcohol, or 0.5% or 1% lidocaine hydrochloride solution, at concentrations specified in the table below.

	Volume of diluent (ml)	Approximate volume of reconstituted solution (ml)	Approximate concentration of cefepime (mg/ml)
Intravenous administration: 500 mg/vial 1 g/vial	5 10	5.6 11.3	100 100
Intramuscular administration: 500 mg/vial 1 g/vial	1.3 2.4	1.8 3.6	280 280

As with other parenterally administered medicinal products, prepared solutions of the drug should be inspected for the presence of particulate matter prior to administration.

Appropriate microbiological investigations should be carried out to identify the causative microorganism(s) and to determine susceptibility to cefepime. However, cefepime may be used as monotherapy prior to identification of the causative microorganism, considering the broad spectrum of antibacterial activity of the drug against both gram-positive and gram-negative microorganisms. In patients at risk of mixed aerobic/anaerobic infection (including Bacteroides fragilis), treatment with cefepime in combination with an agent active against anaerobes may be initiated before identification of the causative organism.

Children.

The drug is administered to children aged 1 month and older.

Overdose.

Symptoms: In cases of significant overdose, especially in patients with impaired renal function, adverse effects are intensified. Symptoms of overdose include encephalopathy accompanied by hallucinations, impaired consciousness, stupor, coma, myoclonus, epileptiform seizures, and neuromuscular excitability.

Treatment: Administration of the drug should be discontinued and symptomatic therapy initiated. Hemodialysis accelerates the elimination of cefepime from the body; peritoneal dialysis is poorly effective. Severe immediate-type allergic reactions require administration of epinephrine and other forms of intensive therapy.

Adverse reactions.

Immune system disorders: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioneurotic edema;

Respiratory system disorders: cough, sore throat, dyspnea;

Cardiovascular system disorders: tachycardia;

Gastrointestinal disorders: nausea, vomiting, dyspepsia, oral candidiasis, taste disturbance, diarrhea, colitis (including pseudomembranous colitis);

Nervous system disorders: headache, insomnia, restlessness, convulsions;

Hepatobiliary disorders: hepatitis, cholestatic jaundice;

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria;

General disorders: asthenia, sweating, fever, vaginitis, erythema, chest pain, back pain, peripheral edema.

Respiratory system disorders: respiratory disturbances;

Gastrointestinal disorders: abdominal pain, constipation;

Nervous system disorders: dizziness, paresthesia;

Cardiovascular system disorders: vasodilation;

General disorders: genital pruritus, fever, and candidiasis;

Immune system disorders: anaphylaxis;

Nervous system disorders: epileptiform seizures.

Local reactions at the site of administration:

Intravenous administration – phlebitis and inflammation;

Intramuscular administration – pain, inflammation.

Post-marketing surveillance:

• Encephalopathy (loss of consciousness, hallucinations, stupor, coma), epileptiform seizures, myoclonus, renal failure;
• Anaphylaxis, including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis, and thrombocytopenia.

Laboratory findings: increased levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, anemia, eosinophilia, prolonged prothrombin time or partial thromboplastin time, and positive Coombs test without hemolysis. Transient increases in blood urea nitrogen and/or serum creatinine, as well as transient thrombocytopenia, were observed in less than 0.5% of patients. Transient leukopenia and neutropenia were also reported.

Possible adverse reactions typical for cephalosporin antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhages, liver function disorders, cholestasis, pancytopenia.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Do not freeze.

Keep out of reach of children.

The reconstituted solution should be stored for up to 24 hours at temperatures not exceeding 30 °C or for up to 7 days at 2–8 °C.

Incompatibility.

Do not mix with other medicinal products in the same container. Use only the diluents specified in the section "Administration and dosage."

Packaging.

One vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Nectar Lifesciences Limited - Unit VI.

Manufacturer's address and location of operations.

Bhatolikalan village, near Jharmajri, E.P.I.P., P.O. Barotiwala, Tehsil Baddi, District Solan, Himachal Pradesh, 174103, India.